Fear memory modulation by incentive down and up-shifts.

Research on retrieval-induced malleability of maladaptive emotional memories has been mostly focused on the effect of drugs and extinction (i.e. post-retrieval extinction). Only a few studies addressed post-retrieval appetitive-aversive interactions. Due to the relevance that the understanding of the interactions between memory content and appetitive or aversive states under retrieval circumstances has for translational research, here we explored the relation between fear (i.e. contextual fear conditioning) and sucrose concentration down (32-4%) or up-shifts (4-32%). These have been reported as methods to induce aversive or appetitive internal states, respectively. We observed that fear expression is differentially susceptible to incentive contrast manipulations depending on the memory stage: acquisition, mere retrieval or retrieval-induced memory malleability. After fear acquisition, freezing behavior and incentive shift direction followed an inverse relation, that is: up-shift decreased fear responding and down-shift increased it. However, freezing behavior remained unaltered when incentive contrast was absent, regardless of the sucrose concentration employed (4-4% and 32-32%). When incentive shifts occurred after mere-retrieval, both negative and positive incentive shifts resulted in increased freezing behavior. Strikingly, this effect was unrelated to the nature of the incentive contrast (either positive or negative), occurring only when animals had no previous experience with the shifted solution. On the other hand, when fear retrieval led to memory malleability, up-shifts in sucrose concentration dampened freezing behavior as much as unshifted controls, whilst down-shift left freezing unaltered. Freezing facilitation was finally achieved after retrieval-induced memory malleability only after prior sampling of the down-shifted solution (i.e. 4% SUC). These results reveal a complex pattern of interactions between memory retrieval and incentive shift-induced internal states.

Apparent reconsolidation interference without generalized amnesia.

Memories remain dynamic after consolidation, and when reactivated, they can be rendered vulnerable to various pharmacological agents that disrupt the later expression of memory (i.e., amnesia). Such drug-induced post-reactivation amnesia has traditionally been studied in AAA experimental designs, where a memory is initially created for a stimulus A (be it a singular cue or a context) and later reactivated and tested through exposure to the exact same stimulus. Using a contextual fear conditioning procedure in rats and midazolam as amnestic agent, we recently demonstrated that drug-induced amnesia can also be obtained when memories are reactivated through exposure to a generalization stimulus (GS, context B) and later tested for that same generalization stimulus (ABB design). However, this amnestic intervention leaves fear expression intact when at test animals are instead presented with the original training stimulus (ABA design) or a novel generalization stimulus (ABC design). The underlying mechanisms of post-reactivation memory malleability and of MDZ-induced amnesia for a generalization context remain largely unknown. Here, we evaluated whether, like typical CS-mediated (or AAA) post-reactivation amnesia, GS-mediated (ABB) post-reactivation amnesia displays key features of a destabilization-based phenomenon. We first show that ABB post-reactivation amnesia is critically dependent on prediction error at the time of memory reactivation and provide evidence for its temporally graded nature. In line with the known role of GluN2B-NMDA receptor activation in memory destabilization, we further demonstrate that pre-reactivation administration of ifenprodil, a selective antagonist of GluN2B-NMDA receptors, prevents MDZ-induced ABB amnesia. In sum, our data reveal that ABB MDZ-induced post-reactivation amnesia exhibits the hallmark features of a destabilization-dependent phenomenon. Implication of our findings for a reconsolidation-based account of post-reactivation amnesia are discussed.

Generalization and recovery of post-retrieval amnesia.

Selective amnesia for previously established memories can be induced by administering drugs that impair protein synthesis shortly after memory reactivation. Competing theoretical accounts attribute this selective post-retrieval amnesia to drug-induced engram degradation (reconsolidation blockade) or to incorporation of sensory features of the reactivation experience into the memory representation, hampering later retrieval in a drug-free state (memory integration). Here we present evidence that critically challenges both accounts. In contextual fear conditioning in rats, we find that amnesia induced by administration of midazolam (MDZ) after reexposure to the training context A generalizes readily to a similar context B. Amnesia is also observed when animals are exposed to the similar context B prior to MDZ administration and later tested for fear to context B but recovers when instead testing for fear to the original training context A or an equally similar but novel context C. Next to their theoretical implications for the nature of forgetting, our findings raise important questions about the viability of reconsolidation-based interventions for the treatment of emotional disorders. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A comparison of behavioral and pharmacological interventions to attenuate reactivated fear memories.

Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate reacquisition. In Experiment 2, memory reactivation was followed by extinction training or administration of midazolam (MDZ) (vs. vehicle) to reduce conditioned fear and attenuate spontaneous recovery. We found both treatments to be equally effective in both experiments. This study suggests that parameters leading to memory destabilization during reactivation are critical to observe long-lasting effects of MDZ or reactivation plus extinction.

An appetitive experience after fear memory destabilization attenuates fear retention: involvement GluN2B-NMDA receptors in the Basolateral Amygdala Complex.

It is known that a consolidated memory can return to a labile state and become transiently malleable following reactivation. This instability is followed by a restabilization phase termed reconsolidation. In this work, we explored whether an unrelated appetitive experience (voluntary consumption of diluted sucrose) can affect a contextual fear memory in rats during the reactivation-induced destabilization phase. Our findings show that exposure to an appetitive experience following reactivation can diminish fear retention. This effect persisted after 1 wk. Importantly, it was achieved only under conditions that induced fear memory destabilization. This result could not be explained as a potentiated extinction, because sucrose was unable to promote extinction. Since GluN2B-containing NMDA receptors in the basolateral amygdala complex (BLA) have been implicated in triggering fear memory destabilization, we decided to block pharmacologically these receptors to explore the neurobiological bases of the observed effect. Intra-BLA infusion with ifenprodil, a GluN2B-NMDA antagonist, prevented the fear reduction caused by the appetitive experience. In sum, these results suggest that the expression of a fear memory can be dampened by an unrelated appetitive experience, as long as memory destabilization is achieved during reactivation. Possible mechanisms behind this effect and its clinical implications are discussed.

Prediction error and trace dominance determine the fate of fear memories after post-training manipulations.

Different mnemonic outcomes have been observed when associative memories are reactivated by CS exposure and followed by amnestics. These outcomes include mere retrieval, destabilization-reconsolidation, a transitional period (which is insensitive to amnestics), and extinction learning. However, little is known about the interaction between initial learning conditions and these outcomes during a reinforced or nonreinforced reactivation. Here we systematically combined temporally specific memories with different reactivation parameters to observe whether these four outcomes are determined by the conditions established during training. First, we validated two training regimens with different temporal expectations about US arrival. Then, using Midazolam (MDZ) as an amnestic agent, fear memories in both learning conditions were submitted to retraining either under identical or different parameters to the original training. Destabilization (i.e., susceptibly to MDZ) occurred when reactivation was reinforced, provided the occurrence of a temporal prediction error about US arrival. In subsequent experiments, both treatments were systematically reactivated by nonreinforced context exposure of different lengths, which allowed to explore the interaction between training and reactivation lengths. These results suggest that temporal prediction error and trace dominance determine the extent to which reactivation produces the different outcomes.

Memory destabilization is critical for the success of the reactivation-extinction procedure.

It has been suggested that, unlike pure extinction which typically results in the return of the fear response under a variety of circumstances, memory reactivation followed by extinction can attenuate the reemergence of conditioned fear. The reactivation-extinction procedure has attracted the attention of basic and clinical researchers due to its potential clinical value for the treatment of psychiatric conditions, such as anxiety and drug abuse disorders. However, mixed results have been achieved so far in replicating and understanding this paradigm. It has been proposed that memory destabilization could be critical in this sense. Using contextual fear conditioning in rats and midazolam as an amnesic agent, we first determined what reactivation conditions are necessary to destabilize the mnemonic trace. After establishing the conditions for memory destabilization, a series of experiments was conducted to determine if destabilization is critical for the success of the reactivation-extinction procedure. Data confirmed the importance of memory destabilization prior to extinction inside the reconsolidation window to attenuate spontaneous recovery and retard reacquisition of conditioned fear. The present report offers a candidate explanation of the discrepancy in results obtained with the reactivation-extinction procedure by different laboratories.